Project Summary Severe mental illnesses (SMI) are the leading cause of global disability and responsible for the largest cost burden among all the non-communicable diseases. One of the major challenges for clinical neuroscience is achieving a mechanistic understanding of the brain circuitry involved in SMI. Such understanding is critical to developing treatments aimed at ameliorating the underlying biological causes of these disorders. Among the psychiatric syndromes, important similarities and differences exist between schizophrenia and bipolar disorder. For instance, mood and psychotic symptoms occur in both disorders and they show significant genetic overlap, yet schizophrenia does not commonly present with the manic and depressive illness phases that are the hallmark of bipolar disorder. These findings suggest that common and disease- specific neural circuitry alterations are associated with schizophrenia and bipolar disorder, which we will examine from a dimensional in addition to a categorical perspective. One of the brain regions implicated in most neuropsychiatric disorders, including schizophrenia and bipolar disorder, is the hippocampal formation (HF). The HF is involved in emotion, stress regulation, and memory formation. This proposal puts forward a model of hippocampal circuitry dysfunction in bipolar disorder to enable systematic hypothesis driven research. The aim of this proposal is to tests this hippocampal circuitry dysfunction model of bipolar disorder by identifying common and disease-specific HF circuitry abnormalities between schizophrenia and bipolar disorder in comparison to healthy volunteers. To achieve this aim, the proposed study will utilize state-of-the-art high-resolution hippocampal cerebral blood volume (CBV) and connectivity mapping. In addition to categorical group comparisons, this study will also examine relationships between these brain imaging measures and dimensional neurocognitive, symptom, and functional outcome profiles. The study builds upon the discovery of the promising novel neuroimaging biomarker for schizophrenia, namely high anterior hippocampal CA1 cerebral blood volume (CBV), assessed using high-resolution CBV mapping; a finding recently replicated. Findings from this line of research are driving new treatment strategies for schizophrenia that use high anterior hippocampal CBV as an imaging based biomarker to assess treatment target engagement. This proposal aims to follow a similar research strategy for bipolar disorder. To our knowledge, the proposed study is first to utilize high-resolution CBV mapping of hippocampal circuitry in bipolar disorder, and first to utilize high-resolution resting state connectivity analyses of hippocampal circuitry in both schizophrenia and bipolar disorder. The proposed research is in line with NIH/NIMH's strategic goal to ?advance novel assays and tools to develop biomarkers of disease and for therapeutic discovery?, and will provide new treatment targets, enable new treatment evaluation, and advance the path towards personalized interventions. Differentiation of common and unique neural substrates associated with schizophrenia and bipolar disorder could be used to predict treatment outcome more effectively and to more effectively assess clinical responses to treatment. Identifying the unique neural substrates associated with bipolar disorder and schizophrenia would also facilitate the development and testing of new treatments for individuals who do not respond well to current treatments. Importantly, they may also hold the promise of early detection and illness prevention.